Nocturnal Gastric Acid Research Articles

1765 Delayed Esophageal Clearance Plays an Important Role in Reflux Symptomology in Scleroderma Patient

INTRODUCTION: We present the case of a patient with advanced scleroderma who experienced symptoms of refractory reflux despite maximum acid suppressing therapy. The use of 24-hour ambulatory esophageal pH impedance measurement led to the diagnosis of esophageal stasis, with subsequent management leading to the improvement of symptoms even with decreased proton pump inhibitor (PPI) dose. CASE DESCRIPTION/METHODS: 70-year old female with history of advanced scleroderma presented with severe retrosternal burning which she described as worst at night. She was taking 60mg Dexlansoprazole daily, an aluminum-magnesium-antacid, as well as an H2 blocker. An outside CT of the chest and abdomen showed a fluid-filled dilated esophagus and upper endoscopy was significant for a small hiatal hernia. The patient initially underwent high resolution manometry (HRM) which showed absent peristalsis. Subsequent pH impedance study identified low impedance in the esophagus with good gastric acid control (gastric acid exposure of 36%) but markedly abnormal gastric acid exposure in the distal esophagus: recumbent time acid exposure 94%, upright acid exposure 3%, and total acid exposure time of 40% despite high dose PPI. Recumbent position acid exposure at the distal esophagus was more prolonged than nocturnal gastric acidity, indicating esophageal stasis was a major factor in symptomatology. The patient was instructed to take her PPI and antacids close to bedtime, sleep with head elevation, and avoid late meals. The patient experienced significant symptom improvement and her PPI dose was successfully decreased. DISCUSSION: Scleroderma is a multiorgan connective tissue disorder affecting the gastrointestinal tract. The most commonly affected portion of the GI tract is the esophagus, with destruction of the smooth muscles of the lower esophageal sphincter and distal esophageal body. Abnormal reflux has been identified in patients with scleroderma on 24-hour pH monitoring in as many as 80% of patients. However, these study findings do not account for delayed esophageal clearance from failed or ineffective esophageal contractions. Patients with systemic sclerosis frequently have large dilated esophagi (pseudoachalasia) with subsequent stasis a major contributing factor for their symptoms. Thus, while pH studies are a useful diagnostic tool in patients with advanced scleroderma, therapeutic measures addressing esophageal stasis, such as nighttime head elevation, should be encouraged.

Gastrointestinal Involvement in Systemic Sclerosis: An Update.

Gastrointestinal Involvement in Systemic Sclerosis: An Update.

Stereoselective Pharmacodynamics and Pharmacokinetics of Proton Pump Inhibitors

Proton pump inhibitors (PPIs) are a group of gastric acid suppressing drugs, they work by irreversibly blocking the H+/K+ ATPase. The structure of PPIs is similar. They all have a similar core with a sulphur atom chiral center combined with different substituent groups. In relation to the sulphur atom chiral center, the pharmacodynamics, pharmacokinetics are diverse between the racemates and their stereoisomers. But there are no reviews outlining the stereoselective pharmacodynamics and pharmacokinetics in PPIs. This review aims to compare the differences between the stereoisomers of PPIs in their pharmacodynamics and pharmacokinetics parameters. And exploring the development directions of PPIs at present. We undertook a search of PubMed databases for PPI research literature including reviews, clinical studies, letters and books, in recent 20 years. The citied papers were high quality, which were carefully screened by authors using standard tools. The data of the pharmacodynamics and pharmacokinetics parameters were selected from the retrieved papers, then making generalization and summary. Ninety-three papers were included in the review, mainly from East Asia, America and Europe. All these papers involved the reviews of PPIs, the pharmacodynamics studies of PPIs and the pharmacokinetics studies of PPIs. Finally, omeprazole, lansoprazole, pantoprazole, rebeprazole and pantoprazole with their enantiomers were discussed in this paper. The findings of this review confirm the differences of pharmacodynamics and pharmacokinetics in the racemates and the stereoisomer of PPIs. Providing longer duration, faster time of onset and better nocturnal gastric acid secretion control are the development directions of new generation PPIs. But, due to debate on the necessity and superiority of these new drugs, more validation studies are needed.

Inadequate response to proton pump inhibitor therapy: causes and patient management tactics

The past decade has been marked by a considerable increase in the number of patients with gastroesophageal reflux disease and gastroduodenal ulcer who show an inadequate response to proton pump inhibitor (PPI) therapy. At the present time, most of the causes diminishing the response have been elucidated. Unfortunately, they cannot always be eliminated by drug therapy; nonetheless, rabeprazole has a number of advantages over other PPIs. The major causes of an inadequate response to PPI therapy are low treatment motivation; nocturnal gastric acid breakthroughs; genetically determined CYP polymorphism; chiefly nighttime symptoms of gastroesophageal reflux disease; non-acid refluxes; hypersensitive esophagus; overweight and obesity.

Dose–response relationships of rabeprazole 5, 10, 20, and 40 mg once daily on suppression of gastric acid secretion through the night in healthy Japanese individuals with different CYP2C19 genotypes

This study was designed to investigate the antisecretory activity of rabeprazole administered once daily in doses of 5, 10, 20, and 40 mg and different cytochrome P450 2C19 (CYP2C19) genotypes on gastric pH in healthy individuals. Additional objectives were delineating the nighttime from the daytime effect and determining the relationships between the pharmacokinetics and pharmacodynamics of rabeprazole. Eight individuals of each of the three genotypes of CYP2C19-homozygous extensive metabolizers (homo-EMs), heterozygous EMs (hetero-EMs), and poor metabolizers (PMs)-were recruited. Twenty-four individuals received a once-daily dose, with dosing interval 24 h of 5, 10, 20, or 40 mg rabeprazole for 5 days in a 4-period crossover fashion. Twenty-four-hour intragastric pH and plasma rabeprazole concentrations were determined on day 5. A dose-dependent increase in median pH and in pH 4 holding time was observed across all CYP2C19 genotypes. When rabeprazole was increased from 20 mg to 40 mg, the differences and 95% confidence intervals (CIs) of nighttime pH 4 holding time between 40 mg and 20 mg in homo-EMs, hetero-EMs, and PMs were 8.0% (-5.0% -21.0%), 28.7% (15.7% -41.6%), and 16.9% (3.9% -29.9%), respectively. The relationship between the area under the plasma concentration-time curve up to the last time point at which rabeprazole was quantifiable (AUC(0-t)) and the pH 4 holding time could be described using a sigmoid maximum effect (E(max)) model. Our data demonstrate that increasing rabeprazole dose up to 40 mg once daily results in an increasing pharmacodynamic effect, which is most apparent for the control of nocturnal gastric acid secretion.

Additional bedtime H2-receptor antagonist for the control of nocturnal gastric acid breakthrough

Nocturnal gastric acid breakthrough (NAB) is defined as intragastric pH<4 for more than one continuous hour overnight. Adding H(2)-receptor antagonists (H2RAs) at bedtime to high-dose proton pump inhibitors is likely to enhance nocturnal gastric pH control and decrease nocturnal gastric acid breakthrough. To assess the effectiveness of additional bedtime H2-receptor antagonists in suppressing nocturnal gastric acid breakthrough and the incidence of adverse effects. We identified eligible trials by searching The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 4, 2008), MEDLINE (1966-August 2008), EMBASE (1980-August 2008) and CINAHL (1982-August 2008). We re-ran the search on CENTRAL (The Cochrane Library Issue 4, 2008), and in MEDLINE, EMBASE and CINAHL in June 2004, July 2005, August 2006 and August 2008. All randomized controlled trials evaluating H2-receptor antagonists for the control of nocturnal gastric acid breakthrough were eligible for inclusion. Two reviewers have independently selected the trials to be included in the review according to the pre-stated eligibility criteria. Disagreements were resolved by a third reviewer. If the data could not be pooled for meta-analysis, a narrative description was provided. 8 small randomized controlled trials were included for meta-analysis. The results show that additional bedtime H2RAs can decrease the prevalence rate of nocturnal gastric acid breakthrough. The results of the analyses for secondary outcomes show that additional bedtime H2RAs can decrease the percentage of time during which pH is less than 4.0 inside the stomach and promote median intragastric pH. We can conclude no implications for practice at this stage. Appropriately designed large-scale randomized controlled trials with long-term follow-up are needed to determine the effects of additional bedtime H2RAs in suppressing nocturnal gastric acid breakthrough.

M1919 Nocturnal Gastric Acid Suppression Is Better Achieved with the Addition of a Nighttime H2-Receptor Antagonist

M1919 Nocturnal Gastric Acid Suppression Is Better Achieved with the Addition of a Nighttime H2-Receptor Antagonist

Nocturnal Gastric Acid Breakthrough Is Not Associated with Night-Time Gastroesophageal Reflux in GERD Patients

Background: Nocturnal acid breakthrough (NAB) is defined as gastric pH below 4 over 60 consecutive minutes at night-time in subjects who take proton pump inhibitors twice daily. The link between NAB and gastroesophageal reflux (GER) episodes has not been investigated using combined multichannel intraluminal impedance and pH-metry (MII-pH). Aims and Methods: The aim was to investigate the relationship between NAB and GER by means of MII and gastroesophageal pH-metry. We reanalyzed MII-pH recordings obtained in patients on twice-daily proton pump inhibitors. Results: Overall 15 eligible recordings were reanalyzed in detail (7 males, 8 females; age 59 ± 10 years, range 36–68 years). NAB was detected in 7/15 (46%) recordings with one NAB in 4 subjects and two 2 NABs in 3 subjects. In 6 of the cases with NAB, reflux symptoms were reported at night, but in no case did these occur in association with NAB. Patients with NAB reported significantly more typical than atypical symptoms (77 times vs. 47 times), whereas patients without NAB reported fewer typical than atypical symptoms (48 times vs. 60; p = 0.011). Over the total 24-hour period, acid reflux was more frequent (9 ± 11 times) in patients with NAB than in patients without NAB (1 ± 0.5 times; p = 0.04). Weakly acid reflux also occurred more frequently (15 ± 9 times) in subjects with NAB than in subjects without NAB (6 ± 4 times; p = 0.02). Weakly alkaline reflux occurred in equal frequencies in subjects with and without NAB (2 ± 4, 0 ± 0.4, respectively). Esophageal acid exposure in the upright position was not different between subjects with NAB and subjects without NAB, but subjects with NAB presented a higher recumbent esophageal acid exposure than subjects without NAB (2.0 ± 2.4 vs. 0%, respectively). Conclusion: Esophageal acid exposure is not increased during NAB episodes. However, over a period of 24 h, patients with NAB presented with increased gastroesophageal reflux. Although NAB and GER are not strongly associated, symptoms of patients with and without NAB are different.

T1653 Helicobacter pylori Infection Is Less Likely in Patients with Inflammatory Bowel Disease: A Meta-Analysis of Relative Risk

BACKGROUND: Nocturnal gastric acid breakthrough (NAB) often occurs during treatment with proton pump inhibitors (PPIs). The existence of NAB with resulting nocturnal acid reflux should be considered when patients with high-grade erosive gastroesophageal reflux disease show resistance to PPIs treatment. On the other hand, in some Helicobacter pylori (H. pylori)-positive subjects, intragastric pH spontaneously neutralizes during the middle of the night without any medication (nocturnal neutralizing of intragastric pH: NN). This probably results from the impairment of the gastric secretory function with the proximal extension of gastric mucosal atrophy. The existence of NN may be an important factor in the pathogenesis of NAB. AIMS: To predict the existence of NN by serum pepsinogen concentrations, relationships between pepsinogen concentrations and NN were investigated. METHODS: 239 subjects were enrolled. Intragastric pH was measured for 24-h, with no antisecretory treatment or antacid administration. NN was defined as intragastric pH > 6 continuously for two thirds or more of the middle-night period (22:00-06:00 h), therefore, subjects were classified into three groups according to the results; NN+: 66.7-100.0%, NN±: 33.4-66.6%, and NN−: 0-33.3%. H. pylori status and serum pepsinogen I and II concentrations were also investigated. Results were expressed as amedian (25th-75th percentile). RESULTS: Of the 125 H. pylori-positive subjects, 25 (20.0%) were NN+, 42 (33.6%) were NN±, and 58 (46.4%) were NN−. Serum pepsinogen I and the pepsinogen I/II ratios were 37.8 ng/mL (15.5-59.8 ng/mL) and 1.9 (0.9-2.6) in NN+, 59.8 ng/mL (48.0-96.3 ng/ mL) and 2.9 (2.4-3.7) in NN±, and 63.7 ng/mL (43.4-78.5 ng/mL) and 3.8 (3.3-4.4) in NN−, respectively. Nineteen of the NN+ subjects (76.0%), 17 NN± (40.5%), and 7 NN− (12.1%) were compatible with the serological atrophy-positive criterion; pepsinogen I ≦ 70 ng/mL and pepsinogen I/II ratio ≦ 3.0. Of the 43 subjects who were compatible with this criterion, 19 (44.2%) were NN+, whereas, of the 82 subjects who were not compatible, only 6 (7.3%) were NN+. On the other hand, of the 114 H. pylori-negative subjects, none was NN+, whereas 100 (87.7%) were NN−.None of the groups withoutH. pylori infection was compatible with this criterion.CONCLUSIONS: The NN phenomenon was only observed in H. pylori-positive subjects with serological gastric mucosal atrophy. Serum pepsinogen I and the pepsinogen I/II ratio could predict the existence of NN. In such subjects, stronger PPIs treatment to prevent NAB might be not necessary.

American Gastroenterological Association Institute Technical Review on the Management of Gastroesophageal Reflux Disease

American Gastroenterological Association Institute Technical Review on the Management of Gastroesophageal Reflux Disease

REFRACTORY GASTRIC ANTRAL ULCER OF UNKNOWN ETIOLOGY

We report a Helicobacter pylori-negative patient with multiple gastric antral ulcers of unknown etiology and without a history of taking non-steroidal anti-inflammatory drugs (NSAIDs). The patient was a 68-year-old woman, and her serum gastrin and pepsinogen levels were within normal limits. The antral ulcers were refractory to treatment with a proton pump inhibitor (PPI) or an H2 receptor antagonist alone. However, since nocturnal gastric acid breakthrough was observed, both drugs were given in combination, which resulted in the healing of the ulcers.

Optimal dose regimens of esomeprazole for gastric acid suppression with minimal influence of the CYP2C19 polymorphism

In this pilot study, we attempted to determine the optimal dosage regimens of esomeprazole for treatment of GERD with minimal influence of the CYP2C19 polymorphism through a study of the pharmacokinetics and pharmacodynamics of esomeprazole given at 3 different dosage regimens with the same total daily dose. Each of the 3 genotypes of CYP2C19, homozygous extensive metabolizers (homEMs), heterozygous EMS (hetEMs), and poor metabolizers (PMs) were recruited in this clinical trial. Subjects were given a placebo followed by the administration of esomeprazole, at a dose of 40 mg once daily (40QD), 20 mg twice daily (20TD), or 10 mg 4 times daily (10Q4D) for 7 days. Twenty-four-hour and nocturnal intragastric pH and plasma esomeprazole concentrations were all determined on day 7. The pharmacokinetic parameters and dynamic characteristics differed among the 3 CYP2C19 genotype groups. With esomeprazole 40QD, gastric acid suppression was insufficient to achieve a therapeutic effect, while 20TD and 10Q4D were found to be effective in controlling both daytime and nocturnal gastric acidity for all 3 genotype groups. It was confirmed that intragastric pH values and plasma esomeprazole concentrations potentially depended on the CYP2C19 genotype status for treatment with esomeprazole. Dosage regimens of divided doses of 20TD or 10Q4D esomeprazole yielded improved antisecretory effects with a minimal influence of CYP2C19 polymorphisms.

Time esophageal pH &lt; 4 overestimates the prevalence of pathologic esophageal reflux in subjects with gastroesophageal reflux disease treated with proton pump inhibitors

BackgroundA Stanford University study reported that in asymptomatic GERD patients who were being treated with a proton pump inhibitor (PPI), 50% had pathologic esophageal acid exposure.AimWe considered the possibility that the high prevalence of pathologic esophageal reflux might simply have resulted from calculating acidity as time pH < 4.MethodsWe calculated integrated acidity and time pH < 4 from the 49 recordings of 24-hour gastric and esophageal pH from the Stanford study as well as from another study of 57 GERD subjects, 26 of whom were treated for 8 days with 20 mg omeprazole or 20 mg rabeprazole in a 2-way crossover fashion.ResultsThe prevalence of pathologic 24-hour esophageal reflux in both studies was significantly higher when measured as time pH < 4 than when measured as integrated acidity. This difference was entirely attributable to a difference between the two measures during the nocturnal period. Nocturnal gastric acid breakthrough was not a useful predictor of pathologic nocturnal esophageal reflux.ConclusionIn GERD subjects treated with a PPI, measuring time esophageal pH < 4 will significantly overestimate the prevalence of pathologic esophageal acid exposure over 24 hours and during the nocturnal period.

How to manage refractory GERD

Patients who are unresponsive to 4-8 weeks' treatment with PPIs twice daily might have so-called refractory GERD. The first investigation these patients should undergo is upper endoscopy to exclude a diagnosis of peptic ulcer disease or cancer and identify the presence of esophagitis. The presence of esophagitis in these patients is suggestive of a pill-induced injury, an autoimmune skin disease involving the esophagus, eosinophilic esophagitis or, less likely, a hypersecretory syndrome or a genotype that confers altered metabolism of PPIs. Refractory reflux syndromes associated with normal endoscopy findings are more problematic to diagnose and further testing may be required, including prolonged 48 h pH testing, impedance measurements (for nonacid reflux), esophageal manometry and gastric function tests. For patients with refractory GERD who do not have esophagitis, possible etiologies include nocturnal gastric acid breakthrough, nonacid GER, missed GER or other diseases such as achalasia, gastroparesis or functional heartburn.

Nocturnal Gastric Acidity and Nocturnal Esophageal Acidity Are Lower with Immediate-Release Omeprazole Than with Lansoprazole or Esomeprazole in GERD Patients Treated with a Proton Pump Inhibitor

Nocturnal Gastric Acidity and Nocturnal Esophageal Acidity Are Lower with Immediate-Release Omeprazole Than with Lansoprazole or Esomeprazole in GERD Patients Treated with a Proton Pump Inhibitor

Effects of low-dose cimetidine on nocturnal acid secretion in healthy subjects

The effects of 100 mg and 200 mg bedtime doses of cimetidine on nocturnal gastric acid secretion were examined in nine healthy subjects in a double blind, placebo controlled, randomised three way crossover study. Treatment was given at 23.00 hours and the gastric contents continually aspirated from midnight until 07.00 hours the following morning. Hourly aliquots were analysed for pH and acid output. Relative to placebo the 100 mg and 200 mg doses of cimetidine respectively increased mean pH by 2.22 and 2.63 units/h (P less than 0.001) with mean acid output decreasing by 0.95 and 0.98 mmol/h (P less than 0.001). Whilst mean pH was higher and mean acid output was lower for 200 mg cimetidine compared to 100 mg cimetidine the difference was not statistically significant. Mean hourly pH was consistently above pH 3 for 100% of the time for both doses of cimetidine whereas mean pH failed to reach this value at anytime on placebo. Low doses of cimetidine taken at bedtime effectively reduced nocturnal gastric acid secretion in healthy individuals.

Comparison of the effects of immediate‐release omeprazole oral suspension, delayed‐release lansoprazole capsules and delayed‐release esomeprazole capsules on nocturnal gastric acidity after bedtime dosing in patients with night‐time GERD symptoms

Gastro-oesophageal reflux disease (GERD) patients on proton pump inhibitors before breakfast or dinner have acid recovery at night. Bedtime immediate-release omeprazole (IR-OME) demonstrated better control of nocturnal pH than pantoprazole before dinner. To compare repeated once daily bedtime dosing of IR-OME, lansoprazole and esomeprazole on nocturnal gastric acidity. Open-label, randomized, crossover study enrolling 54 patients with nocturnal GERD symptoms comparing IR-OME, lansoprazole and esomeprazole at steady state for nocturnal acid breakthrough (NAB), percentage of time with gastric pH > 4 and median gastric pH. Onset of nocturnal acid control with IR-OME was rapid. During the first half of the night, percentage of time with gastric pH > 4 and median gastric pH were significantly higher after IR-OME compared to esomeprazole or lansoprazole (P < 0.001, both comparisons). Over the 8-h night-time period, acid control with IR-OME was significantly better than lansoprazole (P < 0.001), and comparable to esomeprazole. IR-OME reduced NAB compared with esomeprazole and lansoprazole (61% vs. 92% and 92%; P < 0.001, both comparisons). Bedtime IR-OME provided more rapid control of night-time gastric pH and decreased NAB compared with esomeprazole and lansoprazole. Nocturnal acid control with IR-OME was superior to lansoprazole and comparable to esomeprazole. Bedtime dosing with IR-OME may be effective for patients with night-time heartburn.

Comparative Efficacy of Rabeprazole and Pantoprazole in the Control of Nocturnal Gastric Acid Output and Intragastric Acidity—A Randomized, Two-Way Crossover Study

Purpose: Rabeprazole and other proton pump inhibitors (PPI) have been shown to be highly effective in the treatment of gastro-esophageal reflux disease (GERD). However, there has never been a rigorous investigation as to the comparative ability of PPIs when taken as per FDA label to control night-time GERD. In this study, we sought to evaluate the relative efficacies of rabeprazole and pantoprazole in controlling nocturnal gastric acid secretion. Methods: The study was conducted as a double-blinded, randomized crossover study enrolling 23 patients with a history of GERD without previous PPI treatment. The patients first underwent a baseline 12 hour overnight gastric analysis (2000 to 0800) whereby 30 minute samples were collected and assessed for acid output and intragastric pH. The subjects were randomized into 1 of 2 groups to receive either rabeprazole 20 mg or pantoprazole 40 mg on the morning of the next visit (Treatment 1). At that time, a second gastric analysis was completed in the above fashion. Following a 4 week washout, the subjects were given the other study drug (Treatment 2) and a third gastric analysis was completed. Acid output was determined using the titration method. Nocturnal acid breakthrough (NAB) was defined as persistence of gastric pH < 4 for greater than 1 hour between the hours of 22:00 and 06:00. Results: Rabeprazole achieved greater evening and nocturnal acid control compared with pantoprazole (median pH: 4.2 vs 3.9; mean time pH > 4: 5.5 vs 4.5 hours; NAB 50% vs 67%). A significantly greater percentage of patients on rabeprazole maintained an intragastric pH greater than 4.0 for more than 6 hours compared to pantoprazole (47% vs 27%). Rabeprazole achieved greater acid output control compared to pantoprazole (mean acid output:.78 vs 1.18 mEq/hr (p <.005); mean percentage of time acid output < 2: 92% vs 78%). Conclusions: Rabeprazole achieved significantly greater control of evening and night-time acid output, suggesting that it is a highly effective treatment for night-time GERD. In addition, a significantly greater percentage of patients on rabeprazole maintained an intragastric pH > 4 for more than half the study time with fewer incidences of NAB. These results demonstrate for the first time that control of nocturnal gastric acid secretion can be improved with rabeprazole compared to pantoprazole.

Laryngopharyngeal reflux disease with nocturnal gastric acid breakthrough while on proton pump inhibitor therapy

Laryngopharyngeal reflux disease (LPRD) with nocturnal recovery of gastric acid secretion (nocturnal acid breakthrough: NAB) with proton pump inhibitors (PPI) was first reported. A 79-year-old Japanese woman complained of globus pharyngeus and mild heartburn was examined with the use of tetra-probe 24-h pH monitoring. She had been treated for reflux esophagitis (GERD) for 12 months prior to her visit to our office. She took Lansoprazole (30 mg/day) before dinner every day. The tetra-probe 24-h pH monitoring revealed that the recovery of gastric acid secretion occurred 6.5 h after taking the dose of PPI. The intragastric pH dropped < 4 at about 23:00 and remained below that level for 4 h and 50 min. The 24-h pH-metry at each probe showed that the nocturnal recovery of gastric acid secretion with PPI (NAB on PPI) influenced gastroesophageal and laryngopharyngeal refluxes. The symptoms of the pharynx and esophagus disappeared after taking H2 receptor antagonist (H2RA) additionally before bedtime.

Additional bedtime H2‐receptor antagonist for the control of nocturnal gastric acid breakthrough: A Cochrane systematic review

To assess the effectiveness and safety of additional bedtime H(2)-receptor antagonists (H(2)RAs) in suppressing nocturnal gastric acid breakthrough (NAB) via a systematic review. Eligible trials were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library Issue 2, 2004), MEDLINE (January 1966-June 2004), EMBASE (January 1980-June 2004) and CINAHL (January 1982-June 2004). Additional hand-searching was conducted on the proceedings of correlated conferences, eight important Chinese journals and references of all included trials. All randomized controlled trials evaluating H(2)RAs for the control of NAB were eligible for inclusion. The systematic review was conducted using methods recommended by The Cochrane Collaboration. Only two randomized crossover studies, comprising 32 participants, met the inclusion criteria. Because the design, dosage and duration of the treatments were different between the studies, it was not possible to conduct meta-analysis. There were no consistent conclusions found between the two included studies in evaluating H(2)RAs for the control of NAB. No implications for practice at this stage can be concluded. Appropriately designed large-scale randomized controlled trials with long-term follow up are needed to determine the effects of additional bedtime H(2)RAs in suppressing NAB.